325
J. Org. Chem. 1985,50, 325-332 Anal. Calcd for CBHa06: C, 70.00; H, 10.10. Found: C, 69.80; H, 10.00. A similar Baeyel-Villiger reaction starting with the tetraacetate 5d (100 mg) afforded the tetraacetoxy lactone 4d (80 mg): mp 172-174 "C (from hexane); NMR 6 5.24 (1 H, m, 3P-H; W1p = 8 Hz, 5.20 (1 H, dd, 22-H; J = 7 and 3 Hz), 5.08 (1 H, dd, 22-H; J = 3.5 and 3 Hz), 4.86 (1 H, m, 26-H; W1,, = 12 Hz), 4.18 (1 H, dd, 8P-H; J = 10.5 and 8.4 Hz), 2.72 (1 H, dd, 6P-H; J = 10 and 15 Hz), 2.08 (6 H, 8, 2 X CH,CO), 2.05 (3 H, 9, CHSCO), 1.99 (3 H, s, CH,CO), 1.06 (3 H, s, 19-CH3),0.65 (3 H, a, 18-CH3). Anal. Calcd for C36H5S010: C, 66.60; H, 8.70. Found: C, 66.50; H, 8.60. Saponificationof 4d (70 mg) followed by acydification afforded the tetrahydroxy lactone 4b (55 mg): mp 97 "C (sinterizes),146 "C (clarifies) (from hexane); IR 1730, 1710, 1695 cm-l; NMR
(C5D5N)b 4.18 (1 H, dd, 88-H; J = 10.5 and 8.4 Hz), 2.72 (1 H, dd, 6P-H J = 10 and 15 Hz);mass spectrum, m / e 462 (M' - H20). Anal. Calcd for CBHa06: C, 70.00; H, 10.10. Found: C, 69.85; H, 9.90. Acknowledgment. This work was supported by the Italian Research Council (Progetto Finalizzato Chimica Fine e Secondaria). Registry No. 4a, 93782-67-3; 4b, 93805-92-6; 4c, 93782-68-4; 4d, 93782-69-5; 5a, 90965-40-5; 5b, 90965-39-2; 5c, 93782-70-8; 5d, 93782-71-9; 7,93782-72-0; 8,93782-73-1; 8 (detosylated),1012390-7; 9,93806-01-0; 10,93782-74-2; 11,93782-75-3;12a, 72050-71-6; 12b, 72050-72-7; 12b (thioketal),93782-76-4; 13a, 72050-69-2; 13b, 72050-70-5; HSCH&H2SH, 540-63-6.
a-Amino Acids as Chiral Educts for Asymmetric Products. Chirospecific Syntheses of Methyl L-Sibirosaminide and Its C-3 Epimer from L-Allothreonine Peter J. Maurer, Christopher G. Knudsen, Alan D. Palkowitz, and Henry Rapoport* Department of Chemistry, University of California, Berkeley, California 94720
Received June 20, 1984
Efficient syntheses of methyl L-sibirosaminide and its C-3 epimer are described using L-allothreonineas the chiral educt. Amino acylations of organometallicswith the lithium salt of N-(phenylsulfonyl)-L-allothreonine constitute the key carbon-carbon bond-forming steps. The resulting methyl and vinyl ketones are then converted to tertiary alcohols by a second organometallicaddition, and the order of addition controls the stereochemistry at the new chiral center. Stereocontrolled functionalization of the vinyl group then leads to the amino sugars. Elaborationto the C-3 epimer of sibirosamine was achieved via a Pummerer oxidation route, while in the preparation of sibirosamine itself a selective tetraol oxidation route was used. Largely due to their occurrence in important antibiotics,1.2 amino sugars have elicited a substantial interest as synthetic targets for organic ~ynthesis.~ The challenge of creating several adjacent, functionalized chiral centers in a stereo- and enantioselective manner is chemically intriguing, and the emerging importance of the biological role of amino sugars4 adds to the impetus for efficient construction of these molecules. The problem of enantioselection in amino sugar synthesis is usually overcome by choosing a carbohydrate or other chiral p r e c u r ~ o ror , ~occasionally ~~ by resolution of a racemic i~~termediate.~ There appears to be no reported case, however, of the preparation of an amino sugar from an amino acid with retention of the amino group and its chiral integrity. This is probably due to the lack of methods for forming carbon-carbon bonds with amino acids while maintaining optical purity. Recently, we have demonstrated some very versatile methods for performing just these operations. These methods are based on either Freidel-Crafts type amino acylations of aromatic substrates with amino acid chlorides: or on the amino acylations of organometallics with (1) Umezawa, S. Pure AppZ. Chem. 1978,50, 1453. ( 2 ) Reden, J.; Durckheimer, W. Top. C w r . Chem. 1979,83, 105. (3) "Specialist Periodical Reports, Carbohydrate Chemistry"; The Chemical Society: London, 1968-1983; Vol. 1-15. (4) Horton, D.; Wander, J. D. In "The Carbohydrates. Chemistry and Biochemistry"; Pigman, W., Horton, D., Eds.; Academic Press: New York, 1980, Vol. lB, Chapter 16. (5) Pauls, H. W.; Fraser-Reid, B. J.Am. Chem. SOC.1980,102, 3956. (6) Dyong, I.; Schulte, G. Tetrahedron Lett. 1980,21, 603. (7) Schmidt, R. R.; Scheibe, R. Liebigs Ann. Chem. 1980, 1307. (8) Buckley, T. F., 111; Rapoport, H. J. Am. Chem. SOC.1981, 103, 6157.
0022-3263/85/1950-0325$01.50/0
Scheme I. Relationship of Sibirosamine and L-Allothreonine
Hb
i)H
I , si birooamine
2 , open chain form
VZH Y+ HN-X
HN-X
N-blocked-Lallothreonine
HN-X
lithium salts of amino acid^.^,^ The latter method appeared to be aptly suitable as the basis for a chirospecific route to amino sugar syntheses, and we set out to experimentally determine the feasibility of this concept. Sibirosamine (l),derived from the potent antitumor antibiotic sibiromycin,lOJ1was chosen as our prototypical target for several reasons. First, our proposed methodology is made starkly suitable by the structural resemblance of (9) Knudsen, C. G.; Rapoport, H. J. Org. Chem. 1983, 48, 2260. (10)Mesentaev, A. S.; Kuljaeva, V. V.; Rubasheva, L. M. J. Antibiot. 1974, 27, 866. (11) Mesentsev, A. S.; Kuljaeva, V. V. Tetrahedron Lett. 1973, 2225.
0 1985 American Chemical Society
326 J . Org. Chem., Vol. 50, No. 3, 1985
Maurer et al. Scheme 11. Formation of &-Amino Ketones from Threonines
the C-3 to C-6 portion of sibirosamine (open chain form, 2) to L-allothreonine. Second, any epimeric variation a t C-4 and C-5 would be readily accomodated by choosing the proper alternate stereoisomer of threonine, all of which are readily available in optically pure form.I2 Third, the branching methyl at C-3 allows us to explore the formation of two carbon-carbon bonds from the amino acid carboxyl in a stereocontrolled manner. Fourth, sibirosamine has previously been synthesized only as the unnatural D-enantiomer.13J4 Since a carbohydrate precursor was used, the natural L-form may be less accessible by that route. Fifth, a careful stereochemical analysis of our intermediates would allow independent evaluation of the recent revision14 of the relative stereochemistry at C-3 in sibirosamine which was based on established stereoselective synthetic methods and comparison of synthetic and natural materials. Finally, the biological properties of sibiromycin enhance the interest in the availability of its constituent amino sugar. We now report our results which clearly demonstrate the utility and efficiency of the amino acid route to amino sugars.
Results and Discussion a-Amino Ketones from Threonines. The attachment of a methyl group and a two carbon fragment to the carboxyl group of L-allothreonine conceptually provides the complete carbon skeleton of sibirosamine (Scheme I). We considered the vinyl group as a suitable two carbon fragment since (a) it should be easily elaborated by a variety of oxygenation procedures and (b) the vinyl Grignard reagent15 is easily handled. We proposed that the order in which the methyl and vinyl groups were added would be a significant factor in the stereochemical outcome and could be the key to controlling C-3 stereochemistry in our synthesis. Thus both routes shown in Scheme I were to be pursued. On the basis of earlier r e s u l t ~ , ~we , ~chose J~ the phenylsulfonyl groups as the nitrogen protecting group and prepared a quantity of N-(phenylsulfonyl)-L-allothreonine by a modified Schotten-Bauman procedure. The amino acid was prepared by a modified literature procedure. l 2 We had earlier formed the methyl ketone 4 from Nprotected L-threonine (3) by simply stirring with excess methyllithium at room temperature. When these same conditions were applied to N-(phenylsulfonyl)-L-allothreonine ( 5 ) the yield was severely diminished (from 70% to 30%), and the isolation was complicated by the presence of several byproducts. This reaction was improved, however, by treating the lithium salt of 5 (made by adding 250 mol% of methyllithium to a THF solution of 5 ) with excess methylmagnesium iodide and stirring at a slightly higher temperature. Thus the methyl ketone 6 could be obtained from the reaction mixture by a simple crystallization after an aqueous isolation in 64% yield, allowing for 42% recovery of starting material. If the reaction time is lengthened or the temperature raised further to consume all the starting material, then the isolation is more difficult and the yield is not significantly improved. The vinyl ketone 7 was prepared in much the same way by substituting vinylmagnesium bromide for the methyl Grignard reagent. It should be noted that a-epimerization of ketone 6 can take place during the aqueous quench of the reaction mixture if the quenching solution is not kept acidic. This (12) Elliot, D. F. J . Chem. SOC.1950, 62. (13) Parker, K. A.; Babine, R. E. J . Am. Chem. SOC.1982,104, 7330. (14) Parker, K. A.; Babine, R. E. Tetrahedron Lett. 1982, 23, 1763. (15) Normant, H. C. R. Hebd. Seances Acad. Sci. 1954, 239, 1510. (16) Maurer, P. J.; Takahata, H.; Rapoport, H. J . Am. Chem. SOC. 1984, 106, 1095.
Y H
CH-Li
P
4
3
6 6
2,
PhS02
5
A
PhS02
7
Scheme 111. Stereospecific Formation of Tertiary Alcohols
P
6
* 8a
+,-
Sa, R = H loa, R =CH3
/NH PhSOp
PhS02'
7
II
TMSQ --c
12
8b
Sb, R = H lob, R = CH3
leads to contamination of 6 with the enantiomer of 4. The problem, however, is completely avoided by pouring the reaction mixture slowly into excess cold 2 M H3P04. These transformations are outlined in Scheme 11. Formation of Tertiary Alcohols and Stereochemical Analysis. Treatment of ketone 6 with vinylmagnesium bromide provided a single isomer of the tertiary alcohol 8a (Scheme 111). Some of the starting ketone (-20%) was present in the product; therefore, after crystallizing as much 8a as possible from the mixture the mother liquors were resubjected to the Grignard reaction after which the ketone had been completely consumed. With this simple recycle step a total yield of 83% of pure tertiary alcohol was obtained. If the presence of 6 (after the first treatment) is due to enolization, then it is clear that enolization occurs regiospecificallytoward the methyl group since no epimerization takes place. This is in accordance with our observation that ketones 4 and 6 can be added to excess LDA and recovered unchanged after quenching. In order to obtain the epimeric tertiary alcohol, vinyl ketone 7 was treated with methyllithium. This led, unexpectedly, to the nearly exclusive (15/1) formation of
Chirmpecific Syntheses from L-Allothreonine
J. Org. Chem., Vol. 50, No. 3, 1985 327
Scheme IV. Pummerer Route to Episibimsaminide 11
IOb
I3
14b
140
L propyl ketone 11by 1,4addition, the minor product b e i i the desired tertiary alcohol 8b. Treatment of 7 with methyhnagnesium iodide resulted in the formation of an insoluble precipitate and, after quenching, starting material was recovered. Results were more satisfactory after blocking the hydroxyl group. Thus treatment of trimethylsilyl ether 12 with methyllithium in ether provided vinyl tertiary alcohol 8b as the major product. A trace of the epimer 8a was also formed as well as about 20% of 1,4addition product 11. Treatment of 12 with methylmagnesium iodide gave inferior stereaselection (8b/8a, 4/1 compared to 1 2 / 1 for the lithium reagent). In order to determine the relative stereochemistry, the two tertiary alcohols were converted into their corresponding cyclic carbonates 9a and 9b, as shown in scheme 111. A recent report'? appeared t o indicate that in sixmembered cyclic carbonates, an axial substituent would have an 'H NMR absorption at higher field than a similar equatorial substituent. We reasoned that structure 9a should have an axial vinyl group, allowing the other three Substituents to be equatorial. Similarly 9b should have an axial methyl group (at the tertiary alcohol center), allowing three equatorial substituents as well. This analysis is based on the assumption that the cyclic carbonates exist in the chair conformation with the maximum number of equatorial substituents. This rationalization led us to (temporarily) misassign the stereochemistry in structures 98 and 9b and thus 8a and 8b. The correct assignment became clear when Nmethyl derivative 10b was subjected to an X-ray crystallographic structure determination which proved it to have the relative stereochemistry shown in Scheme 111 and Figure 1. The discrepancy with the NMR analysis was also clarified since the crystal structure shows the ring of 10b to be nearly planar. The tertiary carbinol carbon is the only ring atom substantially out of the plane, placing the vinyl group in a pseudoaxial position. The bond from the vinyl group to the ring is nearly perpendicular to the plane of the ring. Thus, while simple methyl-substituted (11) Pihlaja, K.;Teinonen, K.J.:AyrKs, P. Suom. Kemiatil. B 1970, 43.41.
Figure 1. ORTEP drawing of cyclic carbonate 10b from X-ray study. The phenyl group has been deleted for clarity. The numbering system only serves to correlate Figure 1with the data in Table I1 and in the supplementary material, C-4 is equivalent to C-3of the sibirosamine derivatives.
cyclic carbonatesmay exist in stable chair conf0rmati0ns,17 bulkier substituents or heteroatoms apparently perturb the geometry in these systems so that this NMR chemical shift analysis of stereochemistry is unreliable. Elaboration of Cyclic Carbonate 10b t o Methyl N-(Phenylsulfonyl)-3-episibirosaminide(17) via the Pummerer Reaction. Since 10b was first assigned the stereochemistry of 108 ('H NMR assignment, prior to X-ray analysis), it was chosen for elaboration to the amino sugar (Scheme IV). Epoxidation with MCPBA proceeded smoothly to give epoxide 13 as a 2.5/1 ratio of inseparable epimers. This relatively nonstereoselective reagent was used in order to prepare both epimers for a rapid comparative characterization. The plan was to open the epoxides with a sulfur nucleophile in order to investigate the Pummerer route to the aldehyde oxidation state, a route which was applied recently in the synthesis of carhohydrates.'*J9 Treating the epimeric epoxides with thiophenoxide gave completely selective ring opening by attack at the primary carbon, affording phenyl sulfides 148 and 14b. We have no basis for assigning the stereochemistry of the new hydroxyl group, hut for purposes of the discussion we have assumed the major isomer of the 2.511 (18) KO.S.Y.:Lee. A. W. M.: Masamune. S.: Reed. L. A.. III: Shamless, K. B.i Walker, F. J. Science (Woshi&t& D.C.) 1983, 220, 949. (19) Kntsuki, T.;Lee,A. W.M.: Ma, P.; Martin, V. S.;Masamune, S.: Sharplens, K.B.: Tuddenham, D.; Walker, F. J. J . Org. Chem. 1982.47, 1313.
328 J . Org. Chem., Vol. 50, No. 3, 1985 mixture to have structure 14a. The phenyl sulfides were separated by chromatography and individually elaborated as follows. The sulfides were easily oxidized to the sulfoxides 15a and 15b with sodium periodate. These sulfoxides were each clearly mixtures of sulfoxide epimers as expected and as shown by doubling of lH NMR signals. Heating 15a (or its 0-acetyl derivative) in acetic anhydride and sodium acetate as previously described18J9resulted in a complex mixture of products. We suggest that the difficulty lies with the ease of formation of a tertiary carbonium ion under these conditions at the site of the branching methyl group. The hexoses prepared by similar methods were all straight chain molecules.18 Furthermore, the adjacent nitrogen could afford some assistance in carbonium ion formation. Seeking a milder method, we explored the action of trifluoroacetic anhydride (TFAA) on the sulfoxides. Treatment of 15a with excess TFAA at 0 OC to room temperature followed by mercury-assisted methanolysis afforded dimethyl acetal 16 in good yield. The stereochemistry of the hydroxyl group was determined by conversion to the 3-episibirosamine derivative 17. This was accomplished by stirring in methanolic sodium methoxide to cleave the carbonate followed by acidification which instantly led to the methyl glycoside as a mixture of CY- and P-anomers. The N-tosyl analogue of 17 has been previously prepared,14 and the almost total identity of NMR data between the two derivatives (in both anomers) leaves no doubt about the stereochemical assignment at C-2 in 17. The stereochemical arrangement a t C-3, C-4, and C-5 is completely unambiguous based on the X-ray structure of lob. Since 17 corresponds to the stereochemistry that has now been assigned at the C-3 epimer of sibirosamine, this work provides confirmation of the recent reassignment of C-3 stereochemistry in natural ~ibir0samine.l~ Since sulfoxide 15b was also in hand, we sought to elaborate it to the C-2 epimer of 17. However, the Pummerer reaction of 15b led to dimethyl acetal 16, identical with that obtained from 15a. Obviously, some process is in effect which funnels either C-2 epimer of 15 into the single C-2 epimer 16. This could occur as shown in Scheme IV. Here the initial Pummerer rearrangement product 18 (R = COCF3or H) eliminates trifluoroacetic acid to form 19. Readdition of a proton (from either CF3C02Hor CH,OH) to C-2 is then stereospecific, leading only to 16 and none of the C-2 epimer. Since the acetic anhydride mediated Pummerer has no efect on the stereochemistry of the adjacent center,18J9these results must be rationalized on the basis of the better leaving ability of trifluoroacetate compared with acetate itself. While this C-2 funneling process fortuitously leads to the correct C-2 configuration for 3-episibirosamine, we did not wish to rely on this stereomutable approach in the synthesis of the natural isomer of sibirosamine. Therfore, after failing to find a suitable protection scheme which would allow the normal acetic anhydride Pummerer route to succeed with our branched substrates, we turned our attention to a different method. Elaboration of Sa to Sibirosamine via the Selective Oxidation Route. The approach ultimately taken in our synthesis of sibirosamine is shown in Scheme V. This route relies on the stereoselective dihydroxylation of olefin 20 to tetraol21a, followed by the highly selective oxidation of the primary hydroxyl g r o u ~to~afford , ~ ~ lactone 22. The (20) Heyns,K.; Paulsen, H. in “Newer Methods of Preparative Organic Chemistry”; Foerst, W., Ed.; Academic Press: New York, 1963; Vol. 11, p 303.
Maurer et al. Scheme V. Selective Oxidation Route to Sibirosamine
+ OH
PhSOO/N\CH3
2lb
+
PhS02/kCH3
20
21a
1 Phso2Q ‘ oH HO
OH
23, a and B
Hb
bH
22
1 HO OH
L241 25, R = H
26
need for 0-protection was thus completely circumvented, N-Methylation of 8a with methyl iodide and potassium carbonate in acetone led to significant 0-methylation; however, when the solvent was changed to isopropyl alcohol, N-methylated derivative 20 was isolated in 85 % yield as analytically pure crystalline material. Catalytic osmylation22of 20 provided a 4/1 mixture of tetraols 21a and 21b which were easily separable by chromatography. The major isomer (21a) was crystallized to give a 64% yield of analytically pure material. The minor isomer (21b) was isolated in 15% yield as an oil. The assignments are based on the following conversion of 21a to sibirosamine. Platinum-catalyzed oxidationmSz1of tetraol21a with O2 proceeded cleanly to afford lactone 22 in over 90% yield. We have also recently used this process in the conversion of amino alcohols to amino acids with very satisfactory results.16 In this case traces of the anomeric lactols 23 were also noted. Without purification, the lactone was reduced (diisobutylaluminum hydride) to the lactols 23 which were crystallized as the anomeric mixture. The lactols were converted by the action of acidic methanol to a single anomer of methyl glycoside 24 in high yield. ‘H NMR data of 24 were compared with data for the N-tosyl analogue prepared from natural sibiromycin14and found to be in excellent agreement. These spectra were substantially different from either anomer of C-3 epimer 17. The fact that 24 is obtained as a single anomer is also in agreement with the properties of the natural product.14 (21) Heyns, K.; Blazejewicz, L. Tetrahedron 1960, 9, 67. ( 2 2 ) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973.
J. Org. Chem., Vol. 50, No. 3, 1985 329
Chirospecific Syntheses from L-Allothreonine N-Deprotection was accomplished by the rapid reductive cleavage of the phenylsulfonyl group with sodium in liquid ammonia.23 A single anomer of the free amine 25 again was isolated in 82% yield as an oil. The 250-MHz 'H NMR spectrum of t h i s product appears very clean, and t h e high-resolution mass spectrum confirms the molecular formula. In an attempt to obtain the free sugar, the methyl glycoside was t r e a t e d with 6 N HC1. While the product could be detected b y 'H NMR, byproducts also were formed, and the unstable amino sugar could not be isolated in pure form. The 4-amino sugar probably forms pyrroles by cyclization of the amino group with the aldehyde carbon followed b y dehydration and aromatization.
Summary The methyl glycosides of L-sibirosamine and its C-3 epimer have been prepared b y two different routes from the epimeric diols 8a and 8b. It seems likely that both the Pummerer route and t h e selective tetraol oxidation route could be used to prepare either epimer of the amino sugars, although the two routes were selectively applied in t h i s demonstration of the present methodology. Stereocontrol is exerted at each new chiral center formed ((2-2 and C-3), and the stereochemistry at C-4 and C-5 are set b y the choice of starting threonine. Thus, a n y of the eight possible diastereomers of the amino sugar should be available in either the D or L form b y proper application of this process. Amino acids clearly should be useful for o t h e r chirospecific a m i n o sugar syntheses as well. Experimental Section General Methods. Ether and tetrahydrofuran (THF) were
was dissolved in THF (50 mL), cooled to -78 "C, and treated with MeLi (1.29 M, 24 mmol) dropwise over 20 min. The mixture was allowed to warm to room temperature and stirred for 2 h, and then it was poured into 2 M H3P04(25 mL) a t 0 "C and extracted with EtOAc (4X). The organic extracts were combined, washed with NaHC03 (saturated), dried, and evaporated. Crystallization (EtOAc) of the residue provided 0.75 g, 73% yield, of 4: mp 174-176 "C; 'H NMR (5% MezSO-d6in CDCl,) 8 1.08 (d, 3 H, J = 6.2 Hz), 2.19 (s, 3 H), 3.72 (m, 1 H), 4.17 (m, 1 H), 4.27 (d, 1H, J = 6, OH), 6.80 (d, 1H, J = 7, NH), 7.56 (m, 3 H), 7.84 (m, 2 H);[.Iz3D +49.1° (c 1.0, MeOH). Anal. (CllH15N04S)C, H,
N.
(3s,4S )-N-(Phenylsulfonyl)-3-amino-4-hydroxy-2-pentanone (6). N-(Phenykulfony1)-L-allothreonine (5,2.50 g, 9.6 "01) was dissolved in T H F (110 mL), cooled to -78 "C, and treated with MeLi (1.5 M, 24.1 mmol) dropwise over 10 min. After being stirred for 15 min, the mixture was allowed to warm to 0 "C when MeMgI (1.0 M, 24.1 mmol) was added and the mixture was stirred a t 35 "C for 24 h. Isolation as above provided 0.92 g, 37% yield, of 6 mp 145-146 "C (EtOAc/hexanes); 'H NMR (5% MezSO-d6 in CDC13) 6 1.13 (d, 3 H, J = 6.4 Hz), 2.07 (s, 3 H), 3.65 (d, 1 H, J = 6.7, OH), 3.81 (dd, 1H, J1= 7.9, J2 = 4.6), 3.94 (m, 1 H), 6.49 ~ (d, 1H, J = 7.9, NH), 7.54 (m, 3 H), 7.86 (m, 2 H); [ a I z 3+9.6" (c 1.0, MeOH). Anal. (CllN15N04S)C, H, N. From the NaHC03 washings 1.05 g (42%) of 5, unchanged in melting point and [a]D, was recovered by acidification and extraction.
(4S,5S)-N-(Phenylsulfonyl)-4-amino-5-hydroxy-l-hexen%one (7) was prepared in the same manner as ketone 6 by substituting vinylmagnesium bromide for MeMgI. The yield of
7 was 35-40% with about 40% of starting material being recovered: mp 121-122 "C (CHC13/hexanes); 'H NMR 8 1.09 (d, 3 H, J = 6.4 Hz),4.09 (m, 1 H), 4.30 (m, 1H), 5.84 (m, 2 H, includes NH), 6.33 (m, 2 H), 7.53 (m, 3 HI, 7.84 (m, 2 H); [aIz3D+45.4' (c 1.2, MeOH). Anal. (ClZHl5NO4S)C, H, N.
(3S,4S,5S)-N-(Phenylsulfonyl)-4-amino-3,5-dihydroxydistilled from sodium/ benzophenone immediately before use. 3-methyl-1-hexene(8a). Ketone 6 (3.02 g, 11.7 mmol) in T H F Methylene chloride was distilled from P205 Solutions of reaction (30 mL) was added dropwise to vinylmagnesium bromide (70 mixtures in organic solvents were dried over NaZSO4. Organommol in 140 mL THF) a t -10 "C. After 15 min of stirring, the metallic reactions were carried out under Nz, reagents and solvent reaction was allowed to warm to room temperature and stirred being transferred by syringe. Methyllithium and methylan additional 15 min. The mixture was poured into cold 2 M magnesium iodide were used as ether solutions. Vinylmagnesium H3P04(100 mL) and extracted with EtOAc (3X),the extracts were bromide was used as a T H F sol~tion.'~ Platinum oxide (used for washed with NaHC03 (saturated), dried, and evaporated, and the preparing platinum oxidation catalyst) was prepared from amresidue was crystallized (EtOAc/hexanes) to give 2.18 g of 8a. monium chloroplatinate as describedMvZ5 in a platinum vessel.21 The mother liquors were evaporated and the residue was resub'H NMR spectra were recorded in CDC13unless otherwise noted jected to the Grignard reaction (1/3 scale). Aqueous isolation and and are reported in ppm downfield of internal tetramethylsilane chromatography (silica gel, CHC13/EtOAc, 80/20) provided a (6 units). The X-ray crystallographic structure of 10b was defurther 0.60 g of Sa: total yield, 2.78 g, 83%; mp 123-124 "C;'H termined by using the MULTAN 11/82 program. NMR 6 1.20 (d, 3 H,J = 6.5 Hz), 1.24 (s, 3 H), 2.53 (s, 1 H), 2.88 N-(Phenylsulfonyl)-L-threonine (3). L-Threonine (1.19 g, (d, 1 H, J = 7.2), 3.26 (m, 1 H), 4.01 (m, 1 H),4.80 (d, 1 H, J = 10 mmol) was dissolved in H 2 0 (15 mL) and treated with Na2C03 8.9), 4.92 (dd, 1 H, J1 = 10.7, J2 = 0.9), 5.16 (dd, 1 H, J1 = 17.2, (3.18 g, 30 mmol) followed by phenylsulfonyl chloride (2.65 g, 15 J2 = 0.9), 5.52 (dd, 1 H, J1= 10.5, Jz = 17.2), 7.56 (m, 3 H), 7.86 mmol). The mixture was stirred a t room temperature for 5 h, (m, 2 H); [aIz3D-51.5" (c 2.3, MeOH). Anal. (C13H19N04S)C, then washed with EtzO, acidified to pH 2, and extracted with H, N. EtOAc. The solvent was dried and evaporated and the residue (5S,6S)-N-(Phenylsulfonyl)-5-amino-6-hydroxy-4heptawas crystallized (EtOAc/petroleum ether) to yield 1.68 g, 65% none (11). Vinyl ketone 7 (75 mg, 0.28 mmol) in T H F (3 mL) yield, of 3: mp 146-148 "C; 'H NMR (acetone-d6) 6 1.16 (d, 3 H, was added dropwise to MeLi (1.4 mmol in 7 mL THF) at -78 "C. J = 7 Hz), 3.86 (m, 1 H), 4.2 (m, 1 H), 6.29 (d, 1H, J = 9), 7.55 The mixture was stirred a t -78 "C for 1 h, then a t room tem(m, 3 H), 7.86 (m, 2 H); [ a I z 5 D +10.6" (c 3.2, MeOH). Anal. perature for 30 min. The usual isolation provided 80 mg of (CioHi3N05S) C, H, N. material which appeared to be 90% 11 by 'H NMR analysis: 'H N-(Phenylsulfonyl)-L-allothreonine(5). Methyl cis-~-2NMR 6 0.69 (t, 3 H, J = 7.4 Hz), 1.10 (d, 3 H, J = 6.3), 1.38 (m, phenyl-5-methyl-2-oxoline-4-carboxylate (27.2 g, 0.124 mol) was 2 H), 2.20 (m, 2 H), 2.38 (m, 1 H), 4.03 (m, 2 H), 5.91 (d, 1 H, hydrolyzed with 6 N HCl as reported.'2 After removal of benzoic J = 7.7), 7.57 (m, 3 H), 7.83 (m, 2 H). acid and evaporation of the HCl, the residue was dissolved in water ( 4 S , 5 S )-N-(Phenylsulfonyl)-4-amino-5-[ (trimethyl(600 mL), treated with NaZCO3(39.3 g, 0.372 mol) and benzensilyl)oxy]-l-hexen-3-one(12). Vinyl ketone 7 (1.81g, 6.74 mmol) esulfonyl chloride (23.6 mL, 0.186 mol), and stirred vigorously wa8 dissolved in THF (50 mL) and cooled to 0 "C. Trimethylsilyl for 4 h. Isolation was carried out as above to yield 5: 21.8 g, 67% chloride (1.28 mL, 10.1 mmol) was added followed by Et3N (1.41 yield; mp 176-177 "C (lit.16 mp 175-177 "C, D isomer); [aIz3D mL, 10.1 mmol). The mixture was stirred for 20 min at 0 "C and +17.1" (c 2.0, MeOH) (lit.16 [CY],,-16.8", D isomer). (3S,4R)-N-(Phenylsulfonyl)-3-amino-4-hydroxy-2-penta- then distributed between EtOAc and 1 M NaHzPO,, the organic phase was washed (NaHC03, saturated), dried, and evaporated, none (4). N-(Phenylsulfonyl)-L-threonine (3,1.04 g, 4.0 mmol) and the resulting residue of 12 (2.30 g, 100% yield) was sufficiently pure for further use: 'H NMR 8 -0.02 (s, 9 H), +1.25 (d, 3 H, (23) duvigneaud, V.; Behrens, 0. K. J. BioE. Chem. 1937, 117, 27. J = 6.1 Hz), 3.82 (m, 1 H), 4.02 (m, 1 H), 5.48 (d, 1 H,J = 9.3), (24) Adams, R.; Voorhees, V.; Shriner, R. L. in "Organic Syntheses"; 5.64 (dd, 1 H, J1 = 10.5, Jz = l.l),6.04 (dd, 1 H, J1 = 17.4, 52 Gilman, H., Blatt. A. H., Eds.: Wilev: New York. 1950: Collect. Vol. I. = 1.2), 6.32 (dd, 1 H,J1 = 10.5, J2 = 17.4), 7.50 (m, 3 H), 7.80 p 466. (25) Bruce, W. F. J . Am. Chem. SOC.1936,58, 687 (m, 2 H).
330 J. Org. Chem., Vol. 50,No. 3, 1985 (3R ,4S , 5 S ) - N -(Phenylsulfonyl)-4-amino-3,5-dihydroxy3-methyl-1-hexene (8b). To ketone 12 (2.00 g, 5.86 mmol), dissolved in ether (30 mL) and cooled to -78 "C, was added dropwise MeLi (1.5 M, 27 mmol). The mixture was stirred at -78 "C for 1.5 h and then a t room temperature for 30 min. Isolation as before provided a mixture of 8b, 8a, and 11 in a 12/1/4 ratio. Chromatography (silica gel, CH2C12/EtOAc,4/ 1) provided 1.17 g (70% yield) of a 12/1 mixture of 8b/8a which could not be separated until after conversion to the cyclic carbonates. Peaks corresponding to 8a are not listed in the NMR data: 'H NMR 6 1.04 (s, 3 H), 1.16 (d, 3 H, J = 6.5 Hz), 2.68 (s, 1 H), 2.82 (d, 1 H, J = 7.6), 3.31 (m, 1 H), 3.96 (m, 1 H), 5.08 (dd, 1 H, J1= 10.7,JZ = l.O), 5.27 (dd, 1 H, J1 = 17.2, J2 = l.O), 5.88 (dd, 1 H, J1 = 10.7, J2 = 17.2). Cyclic Carbonates 9a and 9b. The diols (either pure 8a or the 12/1 mixture of 8b/8a) were dissolved in CH2C12and cooled to 0 "C. Pyridine (400 mol%) was added, and phosgene was slowly bubbled in for 10 min. After a further 45 min at 0 "C the mixture was flushed with N2 and quenched with aqueous NaHC0, (saturated). The organic phase was dried and evaporated. In this way pure 8a led to 9a which was isolated by chromatography (silica gel, CH2C12/EtOAc,4/1) and crystallization (EtOAc/hexanes) in 75-80% yield. The 12/1 mixture of 8b/8a led to a 12/1 mixture of 9b/9a which was separated by chromatography (silica gel, CH2C12/EtOAc, 9/ 1). Crystallization (EtOAc/hexanes) gave analytically pure 9b in 70-75% yield. 9a: mp 178-181 "C; 'H NMR 6 1.09 (d, 3 H, J = 6.3 Hz), 1.32 (s, 3 H), 3.50 (m, 1H), 4.20 (m, 1 H), 5.07 (d, 1H, J = 9.9), 5.39 (d, 1 H, J = 17.2), 5.42 (d, 1 H, J = l l . O ) , 5.88 (dd, 1 H, 5 1 = 17.2, J2 = 11.0), 7.60 (m, 3 H), 7.92 (m, 2 H); [cY]~,D -83.2" (C 1.1, Me2SO). Anal. (C14H17N05S) C, H, N. 9b: mp 210-214 OC; 'H NMR 6 1.31 (d, 3 H, J = 6.5 Hz), 1.42 (s, 3 H), 3.53 (m, 1 H), 4.30 (m, 1 H), 4.97 (d, 1 H, J = 9.8), 5.00 (d, 1 H, J = 10.8), 5.28 (d, 1 H, J = 17.3), 5.59 (dd, 1H, 51 = 10.8, J2 = 17.3), 7.58 (m, 3 H), 7.83 (m, 2 H); [aIz3D -40.1" ( c 1.2, Me2SO). Anal. (C14H17N05S)C, H, N. N-Methyl Cyclic Carbonate lob. Compound 9b (249 mg, 0.80 mmol) was dissolved in acetone (15 mL) and treated with K2C03(442 mg, 3.2 mmol) and Me1 (0.20 mL, 3.2 mmol). The mixture was stirred a t room temperature for 3 h, filtered, and evaporated, and the residue was distributed between water and EtOAc. The organic phase was dried and evaporated to leave a crystalline mass of 258 mg, 99% yield. Crystallization (CHCl,/hexanes) provided analytically pure material suitable for X-ray structure determination: mp 110-111 "C; 'H NMR 6 1.28 (d, 3 H, J = 5.7 Hz), 1.48 (s, 3 H), 2.91 (s, 3 H), 4.2-4.3 (m, 2 H), 5.27 (dd, 1 H, J1 = 10.9, J2 = 0.9), 5.48 (dd, 1 H, J1 = 17.2, J2 = 0.9), 5.92 (dd, 1 H , J l = 10.9, J2 = 17.2), 7.5-7.7 (m, 3 H), 7.8 D ( c 1.1,MeOH). Anal. (C15H19N05S)C, (m, 2 H); [ a ] 2 3-31.3" H, N. Epoxides 13. Cyclic carbonate 10b (244 mg, 0.75 mmol) and MCPBA (388 mg, 2.25 mmol) were refluxed in CH2C12(10 mL) for 4 days. The mixture was diluted with EtOAc, washed (1 X NaHSO,, 2 X NaHCO,), and dried, the solvent was evaporated, and the residue was purified by radial chromatography (silica gel, CH2C12/EtOAc,9/1) to provide the epoxides 13 as a 2.5/1 epimeric mixture: 243 mg, 95% yield; 'H NMR (major epimer) 6 1.08 (d, 3 H, J = 6.3 Hz), 1.55 (s, 3 H), 2.8-2.9 (m, 1 H), 2.92 (s, 3 H), 3.0 (m, 1 H), 3.4 (m, 1 H), 4.2-4.4 (m, 2 H), 7.5-7.7 (m, 3 H), 7.8-7.9 (m, 2 H); 'H NMR (minor epimer) 6 1.13 (d, 3 H, J = 6.4), 1.49 (s, 3 H), 2.8-3.0 (m, 2 H), 2.91 (s, 3 H), 3.3 (m, 1 H), 4.1 (d, 1 H, J = 8), 4.2-4.4 (m, 1 H), 7.5-7.7 (m, 3 H), 7.8-7.9 (m, 2 H). Phenyl Sulfides 14a and 14b. The 2.5/1 mixture of epoxides 13 (243 mg, 0.71 mmol) was treated with a solution made by adding MeLi (0.071 mmol, 10 mol%) to thiophenol (80.4 pL, 0.78 mmol) in T H F (15 mL). The mixture was stirred a t room temperature for 16 h, the solvent was evaporated, and the residue was dissolved in EtOAc and washed with 10% Na2C03(4X), dried, and evaporated. Radial chromatography (silica gel, EtOAc/ CH2C12,10/90) provided the phenyl sulfides 14a and 14b as a 2.5/1 mixture of 295 mg, 91% yield. The mixture was separated by preparative HPLC (EtOAc/isooctane, 20/80). 14a: mp 116-117 OC; [aI2*D -2.8" ( c 0.7, MeOH); 'H NMR 6 1.01 (d, 3 H, J = 5.9 Hz), 1.29 (s, 3 H), 2.82 (s, 3 H), 3.09 (dd, 1 H, J1 = 7.8,JZ = 14.0), 3.33 (dd, 1 H, 51 = 6.6,52 = 14.0), 4.09 (d, 1 H, J = 9.2), 4.2 (m, 1 H), 5.36 (dd, 1 H, Jl = 6.6, J2 = 7.7),
Maurer e t al. 7.3-7.5 (m, 3 H), 7.5-7.7 (m, 5 H), 7.8-8.0 (m, 2 H). Anal. (C21H25NOsS2) C, H, N. 14b: mp 173-175 "C; [a]24D -41" ( c 0.5, MeOH); 'H NMR 6 0.97 (d, 3 H, J = 6.2 Hz), 1.41 (s, 3 H), 2.85 (s, 3 H), 3.61 (d, 2 H, J = 7.0), 4.15 (m, 1 H), 4.31 (d, 1 H, J = 9.4), 4.48 (t, 1 H, J = 7.0), 7.3-7.7 (m, 8 H), 7.8-8.0 (m, 2 H). Anal. (CzlH2sN0,&) C, H, N. Sulfoxides 15a. Phenyl sulfide 14a (91 mg, 0.20 mmol) was dissolved in MeOH (12 mL) and treated with NaIO, (67 mg, 0.32 mmol) in H 2 0 (2 mL). The mixture was stirred a t room temperature for 24 h and then distributed between water and CHC13. The organic phase was dried and evaporated, and the residue was purified by radial chromatography (silica gel, EtOAc/CH2C12,l/l). The product (94 mg, 100% yield), which was obtained as an oil, was a 2/1 mixture of sulfoxide epimers: 'H NMR (major epimer) 6 0.82 (d, 3 H, J = 6.1 Hz), 1.39 (s, 3 H), 2.82 (s, 3 H), 2.9-3.2 (m, 2 h), 3.92 (d, 1 H, J = 9.2), 4.2 (m, 1 H), 5.88 (dd, 1 H, J1= 2.6, J2 = 10.5), 7.5-7.9 (m, 10 H); 'H NMR (minor epimer) 6 0.84 (d, 3 H, J = 5.9), 1.43 (s, 3 H), 2.79 (s, 3 H), 3.2-3.4 (m, 2 H), 3.89 (d, 1 H, J = 8.5), 4.2 (m, 1 H), 5.63 (dd, 1 H , J1= 4.7, J z = 7.81, 7.5-7.9 (m, 10 H). Sulfoxides 15b. These were obtained as a 3/2 mixture of sulfoxide epimers from 14b in the same manner as above: 'H NMR (major epimer) 6 0.84 (d, 3 H, J = 5.9 Hz), 1.52 (s, 3 H), 2.77 (s,3 H), 3.05 (dd, 1 H, 51 = 1.8, J2 = 13.0), 3.87 (dd, 1 H, J1= 11.3,J2 = 13.0),3.94 (d, 1 H, J = 9.9), 4.1 (m, 1 H), 5.02 (dd, 1 H, J1 = 11.1, J2 = 1.8), 7.4-7.9 (m, 10 H); 'H NMR (minor epimer) 6 0.89 (d, 3 H, J = 5.7), 1.43 (s,3 H), 2.78 (s, 3 H), 3.2-3.5 (m, 2 H), 4.1 (m, 1 H), 4.12 (d, 1 H, J = lo), 4.59 (dd, 1 H, J1 = 4, J2 = 9), 7.5-7.9 (m, 10 H). Dimethyl Acetal 16. Sulfoxide 15a (18 mg, 0.038 mmol) was dissolved in CHzClz (4 mL), cooled to 0 "C, and treated with trifluoroacetic anhydride (95 fiL, 0.67 mmol). The solution was stirred a t 0 "C for 30 min and then at room temperature for another 30 min. Methanol (5 mL) was added, followed by methanesulfonic acid (1drop) and mercuric acetate (30 mg). The mixture was stirred a further 10 min, then poured into saturated NaHC03, and extracted with CHC1,. The extracts were dried and evaporated and the residue was purified by radial chromatography (silica gel, EtOAc/CH2C12,15/85) to give the pure dimethyl acetal 16, which crystallized on standing: 12 mg, yield 78%; mp 156-157 "C; [a]24D -20" (c 0.2, MeOH); 'H NMR 6 0.99 (d, 3 H, J = 6.1 Hz), 1.32 (6, 3 H), 2.83 (s, 3 H), 3.48 ( 8 , 3 H), 3.51 (s, 3 H), 4.11 (d, 1 H, J = 9.3), 4.2-4.35 (m, 1 H), 4.49 (d, 1 H, J = 7.7), 5.28 (d, 1 H, J = 7.7), 7.5-7.7 (m, 3 H), 7.8-7.9 (m, 2 H). Anal. (Ci,HzsNOsS) C, H, N. Under the same conditions, sulfoxide 15b gave the same dimethyl acetal 16. Methyl N-(Phenylsulfonyl)-3-episibirosaminide, a- and B-Anomers (17). Dimethyl acetal 16 (8 mg, 19 pmol) was dissolved in MeOH (2 mL) and treated with sodium methoxide (1 M in MeOH, 38 pL). The mixture was stirred a t room temperature for 24 h, then methanesulfonic acid (3 drops) was added, and stirring was continued another 15 min. The mixture was poured into NaHC03 (saturated) and extracted with CHCl,, and the extracts were dried and evaporated to give a mixture of anomers of 17 as an oil: 7 mg, 100% yield; 'H NMR ( a anomer) 6 1.04 (d, 3 H, J = 6.2 Hz), 1.19 (s, 3 H), 2.95 (s, 3 H), 3.44 (s, 3 H), 3.48 (br s, 1 H), 3.9-4.2 (m, 1 H), 4.06 (d, 1 H), 4.68 (br s, 1 H), 7.4-7.65 (m, 3 H), 7.8-7.9 (m, 2 H); 'H NMR ( p anomer) 6 0.83 (d, 3 H, J = 6.1), 1.40 (s, 3 H), 2.93 (9, 3 H), 3.37 (br s, 1 H), 3.51 (s, 3 H), 3.88 (d, 1 H, J = l O . l ) , 3.9-4.2 (m, 1 H), 4.79 (d, 1 H, J = l.O), 7.4-7.65 (m, 3 H), 7.8-7.9 (m, 2 H). (3S,4S ,5S)-N-(Phenylsulfonyl)-N,3-dimethyl-4-amino3,5-dihydroxy-l-hexene(20). Diol 8a (2.00 g, 7.01 mmol), K2CO3 (4.84 g, 35 mmol), and Me1 (2.18 mL, 35 mmol) were stirred in isopropyl alcohol (125 mL) a t 65 "C for 36 h. The solvent was evaporated, the residue was partitioned between water and CHCl,, the aqueous phase was reextracted with CHC13,and the organic phases were combined, dried, and evaporated. The residue was chromatographed (silica gel, EtOAc/CHCl,, 1/91 and crystallized to give 20: 1.75 g, 83% yield; mp 96-97 "C; 'H NMR 6 0.96 (d, 3 H, J = 6.2 Hz), 1.41 (s, 3 H), 2.75 (s, 3 H), 3.14 (d, 1 H, J = 3.2, OH), 3.27 (s, 1 H, OH), 3.91 (d, 1H, J = 8.8), 4.05 (m, 1 HI, 5.14 (dd, 1 H, J1 = 1.0, J2 = 10.8), 5.35 (dd, 1 H, J , = 1.0, J z = 17.2),6.01 (dd, 1 H , J l = 10.8,J2 = 17.41, 7.5-7.7 (m, 3 H), 7.8-7.9
Chirospecific Syntheses from L-Allothreonine (m, 2 H); [o!]23D-39.1" (c 1.6, MeOH). Anal. (C14H21NOlS)C, H, N. ( 2 5 , 3 R , 4 5 , 5 S ) - a n d (2R,3R,45,5S)-N-(Phenylsulfonyl)-N,3-dimethyl-4-aminohexane-lf,rols (21a and N-methyhorpholine a n d 21b). Olefin 20 (1.48 g, 4.94 "01) N-oxide.H,O (1.34 g, 9.89 mmol) were dissolved in acetone/H20 (8/1, 120mL), treated with OBO, (25 mg/mL in tert-butyl alcohol, 5 mL, 0.49 mmol), and stirred at room temperature for 48 h. Sodium dithionite (1.72 g), in a small amount of water was added and stirring was continued for 30 min. The precipitated osmium was filtered off, the filtrate was evaporated, and the residue was dissolved in 0.25 M H3P04 and extracted with CHC13/i-PrOH (4/1,5X). The solvent was dried and evaporated, and the residue was chromatographed (silica gel, EtOAc/CHC13, 1/1elutes 21a; EtOAc elutes 21b). The first fraction was crystallized (EtOAc/hexanes) to give 21a: 1.05 g, 64% yield; mp 179-180 "C; 'H NMR (CD,OD) 6 1.01 (d, 3 H, J = 6.3 Hz), 1.30 (s, 3 H), 3.01 (s, 3 H), 3.59 (m, 1 H), 3.88 (m, 4 H), 7.5-7.7 (m, 3 H), 7.8-7.9 (m, 2 H); [o!]=D -17.0" (c 2, MeOH). Anal. (C14H23NOSS)c, H,
N.
The second fraction gave 21b as an oil: 0.27 g, 16% yield; 'H NMR (CD,OD) 6 1.00 (d, 3 H, J = 5.8 Hz, 1.28 (8, 3 H), 2.90 (s, 3 H), 3.57-3.81 (m, 2 H), 4.03 (m, 2 H), 7.5-7.7 (m, 3 H), 7.8-7.9 (m, 2 HI. (2R ,3R , 4 S ,5S )-N-(Phenylsulfonyl)-N,3-dimethyl-4amino-2,3,5-trihydroxyhexanoicAcid &Lactone (22). Platinum oxide (395 mg) was reduced in H20 (30 mL) under 45 psi H2 pressure for 20 min. The catalyst suspension was added to 21a (790 mg, 2.37 mmol) in H 2 0 (180 mL), oxygen was passed through the stirred mixture a t 60 "C for 2 h, the catalyst was filtered off, NaCl(3 g) was added, and the solution was extracted with CHC13/i-PrOH (4/1,5X). The extracts were dried and the solvents were evaporated to leave 706 mg (91% yield) of 22 containing a trace of lactols 23. The product was used in the next step without further purification: 'H NMR 6 1.07 (d, 3 H, J = 6.1 Hz), 1.30 (s, 3 H), 2.84 (s, 3 H), 4.14 (d, 1 H, J = 9.8), 4.19 (s, 1H), 4.4 (m, 1 H), 7.5-7.7 (m, 3 H), 7.8-8.0 (m, 2 H); [o!]23D -74.0" (c 1.3, MeOH). N-(Phenylsulfony1)sibirosamine(23). Lactone 22 (639 mg, 1.94 mmol), dissolved in T H F and cooled to -45 "C, was treated with diisobutylaluminum hydride (1.4 M in hexane, 6.93 mL, 9.7 mmol). The solution was stirred a t -45 "C for 3.5 h and then quenched with MeOH (20 mL) containing CH3S03H (2 mL). After warming to room temperature, the mixture was poured into CHCl, and excess saturated NaHCO,, the mixture was filtered, and the layers were separated. The aqueous phase was reextracted with CHC1, and CHCl,/i-PrOH (4/1), the combined extracts were dried, and the solvents were evaporated to leave a residue (600 mg) which was crystallized (EtOAc/hexanes) to give 485 mg (75% yield) of the lactols as a nearly 1/1 a,p-anomeric mixture: mp 180-188 "C; 'H NMR 6 0.53 (d, 3 / 2 H, J = 6.2 Hz),0.59 (d, 3/2 H, J = 5.9), 1.32 (s, 3 / 2 H), 1.45 (s, 3 / 2 H), 2.87 (s, 3/2 H), 2.92 (s, 3 / 2 H), 3.60 (br s, 1 H), 3.72 (m, 1 H), 4.0-4.2 (m, 1 H), 4.81 (br s, 1/2 H), 5.23 (br s, 1/2 H), 7.5-7.7 (m, 3 H), 7.8-7.9 (m, 2 H); CY]^,^ -46.6" (c 1.4, MeOH). Anal. (C14H2,N06S)C, H, N. Methyl N-(Phenylsulfony1)sibirosaminide (24). N-(Phenylsulfony1)sibirosamine (23, a- and P-anomers, 339 mg, 1.02 mmol) was dissolved in MeOH (8 mL), CH3S03H (5 drops) was added, and the solution was refluxed for 45 min, then poured into NaHC0, (saturated), and extracted with CHCl, and CHC13/iPrOH (4/1). The extracts were dried and evaporated and the residue was chromatographed (silica gel, CHC13/EtOAc, 4/1) and crystallized (EtOAc/hexanes) to give 315 mg, 89% yield, of 24: mp 115-116 "C; 'H NMR 6 0.53 (d, 3 H, J = 5.7 Hz), 1.38 (s, 3 H),2.90 (s, 3 H), 3.25 (br s, 1H, OH), 3.34 (s, 3 H), 3.55 (d, 1H, J = 1.3), 3.69 (d, 1H, J = 9.9), 3.74 (m, 1 H), 4.33 (br s, 1H, OH), 4.69 (d, 1 H, J = 1.21, 7.5-7.7 (m, 3 H),7.8-7.9 (m, 2 HI; [ n ] 2 3 ~ -89.3" (c 1.8, MeOH). Anal. (C1,H2,NO6S) C, H, N. Methyl Sibirosaminide (25)." Phenylsulfonyl derivative 24 (148 mg, 0.43 mmol) was placed in a flask equipped with a dry ice condensor. Anhydrous ammonia (10 mL) was condensed into the flask, small pieces of sodium were added to the stirred solution until a deep blue color persisted for 5 min, and then NH4Cl was added to destory the blue color. The ammonia was evaporated with a stream of nitrogen, and the residue was dissolved in saturated NaHC03 (2 mL) and extracted with CHC1, and CHC13/
J . Org. Chem., Val. 50, No. 3, 1985 331 Table I. Crystal and Data Collection Parameters for Compound lob, Cl5HlSNOIS Crystal Parameters at 25 "C",* a = 8.2136 (5) A space group, P2,212, (No. 19) b = 11.1000 (14) 8, formula weight = 325.39 amu c = 18.2287 (21) 8, 2=4 size of crystal, 0.28 X 0.30 X 0.32 mm V = 1661.9 (3) d(obsd) = d(ca1cd) = 1.30 g ~ m ' ~ @(calcd)= 2.06 cm-' Data Measurement Parametersz6 radiation, Mo Ko! (A = 0.71073 A) monochromator, highly oriented graphite (20 = 12.2') detector, crystal scintillation counter with PHA reflections measured, +h,+k,+l 20 range, 3-45 scan type: 0-20 scan speed, 0.60-6.7 (0 deg/min) scan width, A0 = 0.5 + 0.347 tan 0 background, measured over an additional 0.25 (A@ at each end of the scan vertical aperture = 3.0 mm aperture - crystal = 173 mm horizontal aperture = 2.0 + 1.0 tan 0 mm (variable) no. of reflections collected, 1288 no. of unique reflections, 1269 intensity standards, (4,0,0), (0,8,0), (0,0,12),measured every 2 h of X-ray exposure time; over the data collection period no decrease in intensity was observed orientation, 3 reflections were checked after every 250 measurements; crystal orientation was redetermined if any of the reflections were offset from their predicted positions by more than 0.1"; reorientation was not needed during data collection "Unit cell parameters and their esd's were derived by a leastsquares fit to the setting angles of the unresolved Mo K a components of 24 reflections with 20 between 27O and 31O. *In this and all subsequent tables and esd's of all parameters are given in parentheses, right justified to the least significant digit(s) given. i-PrOH (4/1) alternating for a total of eleven extractions. The dried (K2C03)extracts were evaporated to leave a residue of nearly pure amine 25 as an oil: 72 mg, 82% yield; 'H NMR (CD,OD) 6 1.21 (s, 3 H), 1.27 (d, 3 H, J = 6.3 Hz), 2.35 (d, 1 H , J = 9.9), 2.48 (s, 3 H), 3.32 ( 8 , 3 H), 3.36 (d, 1 H, J = 1.3), 3.56 (dq, 1 H, J1= 6.3, J2 = 9.9), 4.59 (d, 1H, J = 1.0);in D20/DCl the 'H NMR spectrum is essentially identical with that reported" for the glycoside hydrochloride; [o!]23D -77.0" (c 1.5, MeOH); mass spectrum, exact mass calcd for C9H19NO4 m / z 205.1314, found 205.1317. SibirosamineSHCl (26). Methyl sibirosaminide (25, 10 mg, 50 wmol) was dissolved in 6 N DCl in D20. The solution was heated a t 60 "C and monitored by 'H NMR ever 2 h. After 6 h, the methyl glycoside was cleaved to the extent of about 50%. The anomeric protons of the free sugar appeared as slightly broadened singlets at 5.05 and 5.17 ppm in a ratio of 2/1. Other signals were obscured by byproducts and starting material. Further heating or storage of the sample led to continually decreasing amounts of product with formation of UV absorbing (254 nm) material. X-ray Crystallographic Analysis. Large, clear, colorless crystals of 10b were obtained by slow crystallization from CHC13/hexanes. Fragments cleaved from some of these crystals were mounted on glass fibers using polycyanoacrylate cement. Preliminary precession photographs indicated orthorhombic Laue symmetry and yielded preliminary cell dimensions. Systematic absences were consistent only with space group P212121(No. 19). The crystal used for data collection was then transferred to our Enraf-Nonius CAD-4 diffractometer26 and centered in the beam. Automatic peak search and indexing procedures yielded the same reduced primitive cell as found from the photographs. The final cell parameters and specific data collection parameters are given in Table I. (26) Instrumentation at the University of California chemistry department X-ray crystallographic facility (CHEXRAY) consists of two Enraf-NoniusCAD-4 diffractometers,one controlled by a DEC PDP 8/a with an RK05 disk and the other by a DEC PDP 8/e with an RLOl disk. Both use Enraf-Nonius software as described in the CAD-4 Operation Manual, Enraf-Nonius, Delft, Nov, 1977, updated Jan, 1980.
332 J . Org. Chem., Vol. 50, No. 3, 1985 Table 11. Positional Parameters and Their Estimated Standard Deviationsa atom I u 2 B, AZ S 0.00987 (9) -0.28966 (7) 0.24879 (4) 4.24 (1) 01 -0.0962 (3) -0.3982 (2) -0.0037 (1) 6.06 (6) 02 0.1756 (3) -0.3698 (2) 0.0156 (1) 5.43 (5) 03 0.0623 (4) -0.3279 (3) -0.0898 (1) 8.03 (7) 04 0.0682 (3) -0.1747 (2) 0.2711 (1) 5.81 (5) 05 0.0838 (3) -0.3958 (2) 0.2778 (1) 5.38 ( 5 ) 0.1602 (1) 4.39 (5) N 0.0261 (3) -0.2950 (2) Cl 0.0488 (5) -0.3649 (3) -0.0280 (2) 5.69 (8) C2 -0.1366 (4) -0.4190 (3) 0.0736 (2) 4.58 (7) C3 0.0127 (4) -0.4115 (2) 0.1233 (1) 3.82 (6) C4 0.1681 (4) -0.4441 (3) 0.0818 (2) 4.59 (7) C5 -0.2260 (5) -0.5365 (4) 0.0767 (2) 7.0 (1) C6 0.3217 (4) -0.4128 (4) 0.1234 (2) 6.48 (9) C7 0.1718 (5) -0.5747 (3) 0.0609 (2) 6.17 (9) C8 0.2125 (7) -0.6172 (4) -0.0036 (2) 9.5 (1) C9 0.0161 (5) -0.1823 (3) 0.1169 (2) 5.70 (8) C10 -0.1983 (3) -0.2972 (3) 0.2707 (2) 4.05 (6) C11 -0.2617 (5) -0.3963 (4) 0.3039 (3) 7.4 (1) C12 -0.4248 (6) -0.3986 (4) 0.3233 (3) 9.1 (1) C13 -0.5208 (4) -0.3049 (4) 0.3082 (2) 7.1 (1) C14 -0.4620 (4) -0.2099 (4) 0.2725 (2) 7.08 (9) C15 -0.2992 (4) -0.2025 (4) 0.2532 (2) 5.80 (8) Anisotropically refined atoms are given in the form of the htropic equivalent thermal parameter defined as (4/3)[a2B(1,1)+ b2B(2,2)+ c2B(3,3) + ab(cos r)B(1,2) + ac(cos P)B(1,3) + bc(cos a)B(2,3)] S t r u c t u r e Determination. The 1288 raw intensity &a =re converted to structure factor amplitudes and their eetjmra(ed standard deviations by correction for scan speed, backgt&, and Lorentz and polarization effectn.n-ae No correctjonfor -tal decomposition was necessary. Inspection of the azimuthrl8~ltl dataMshowed a variation Imb/Ima = 0.97 for the average curve. No correction for absorption was applied. Removal of systematically absent data left 1269 unique data. The structure was solved by using MULTAN 11/8p and refined via standard least-squares and Fourier techniques. The enantiomer was fixed by reference to the known absolute configuration around C-2 and C-3. In a difference Fourier map calculated following refinement of all non-hydrogen atoms with (27) All calculations were perfwmed on a PDP 11/60eqvippisd with 128 kilowords of memory, twin RK07 28 MByte disk drives, 7i”emt.e~ printer/plotter and TU10 tape drive with locally modified Nonius-SDP8 software operating under RSX-I1M. (28) Structure Determination Package User’sGuide, 1982,B. A. Frenz and Associates, College Station, TX 77840. (29) The data reduction formulae are
Maurer e t al. anisotropic thermal parameters, peaks corresponding to the expected positions of most of the hydrogen atoms were found. Hydrogens were included in the structure factor calculations in their expected positions based on idealized bonding geometry but were not refined in at least squares. They were assigned isotropic thermal parameters 1-2A2 larger than the equivalent Biso of the atom to which they were bonded. Inspection of the low-angle, high-intensity data indicated that a correction for secondary extinction was necessary. A secondary extinction coefficient31 was included in the least-squares refinement. The final residuals= for 200 variables refined against the 1123 data for which P > 30(F) were R = 2.81%, w R = 4.04% and GOF = 1.823. The R value for all 1269 data was 3.63%. The quality minimized by the least-squares program was Cw(pd- pc1)2, where w is the weight of a given observation. The p factor,32used to reduce the weight of intense reflections, was set to 0.035 for the final cycles of refinement. The analytical forms of the scattering factor tables for the neutral atoms were used33 and all non-hydrogen scattering factors were corrected for both the real and imaginary components of anomalous d i s ~ e r s i o n . ~ ~ Inspection of the residuals ordered in ranges of sin O/A, IF& and parity and value of the individual indexes showed no unusual features 01 trends. the largest peak in the final difference Fourier m a p k d an electron density of 0.13 e-/A3. ThQ positional parameters of the non-hydrogen atoms are given in Table 11.
Acknowledgment. The crystal structure analysis was performed by Dr. F. J. Hollander, staff crystallographer at the University of California, Berkeley, X-ray Crystall m * i c Facility (CHEXRAY). B*gjsshy NO.3, 93474-55-6; 4, 93474-56-7; 5, 93474-57-8; 6, 93474-W-9; 7, 93474-59-0; 8a, 93474-60-3; 8b, 93601-09-3; 9a, 9347443-4;Sib, 93Wl-10-6; lob, 93474-62-5; 11, 93474-63-6; 12, 93474-64-7; 13 (issmer A), 93474-65-8; 13 (isomer B), 93601-11-7; 14s)93434-66-9; 14b,93601-12-8; 15a (isomer A), 93474-67-0; 15a (isomer B), 513601-13-9; 15b (isomer A), 93601-14-0; 15b (isomer B), 93601-15-1; 16,93474-68-1; 17 (a-isomer), 93474-69-2; 17 (0isomer), 93474-70-5; 20, 93474-71-6; 21a, 93474-72-7; 21b, 93601-16-2; 22,93474-73-8; 23 (a-isomer), 93474-749; 23 (@-isomer), 93474-75-0; 24, 93474-76-1; 25, 93601-17-3; 26, 93601-18-4; Lthreopine, 72-19-5; methyl cis-~-2-phenyl-5-methyl-2-oxazoline4-carboxylate, 82659-84-5; vinylmagnesium bromide, 1826-67-1; thiophswl, 108-98-5; L-allothreonine, 28954-12-3; MeMgI, 91764-6. Su@&”tary Material Available: Tables of general t e m w a t u r e factor expressions, thermal vibration amplitudes, unrefined hydrogen positional parameters, intramolecular distancea, intramolecular angles and torsional angles (4 pages). Ordering information is given on any current masthead page.
(31) Zachariesen, W. H. Acta Crystallogr. 1963, 16, 1139. (32)
where C is the total count in the scan, B the s u m of the two background counts, w the scan speed used in deg/min, and - 1=
LP
sin 28 (1 + cos2 28,) 1 + cos2 28, - sin228
is the correction for Lorentz and polarization effects for a reflection with scattering angle 28 and radiation monochromatized with a 50% perfect single-crystal monochrometer with scattering angle 28,. (30) Reflections used for azimuthal scans were located near x = 90’ and the intensities were measured at IOo increments of rotation of the crystal about the diffraction vector.
where no is the number of observations, n, the number of variable parameters, and the weights w were given by
where p is the factor used to lower the weight of intense reflections. (33) Cromer, D. T.; Waber, J. T. “International Tables for X-ray Crystallography”;The Kynoch Press: Birmingham, England, 1974;Vol. IV, Table 2.2B. (34)Cromer, D. T. Reference 33, Table 2.3.1.
